The present invention is concerned with 6-alpha- and 6-beta-[(C.sub.1 -C.sub.4)alkoxyaminomethyl and benzyloxyaminomethyl]penicillanic acid 1,1-dioxides, pharmaceutically acceptable salts thereof and conventional esters thereof hydrolyzable under physiological conditions, all of which are useful in medicine as beta-lactamase inhibitors; intermediates and processes therefor; and a process for the conversion of various of the present compounds to 6-alpha- and 6-beta-(aminomethyl)penicillanic acid 1,1-dioxides and derivatives.
beta-Lactamase inhibitors represent an important class of medicinal agents, useful in combination with conventional beta-lactam antibiotics (penicillins and cephalosporins) against microorganisms resistant or partially resistant to those antibiotics through production of beta-lactamase enzymes.
Compounds (and corresponding hydrolyzable esters) which are known to possess desirable beta-lactamase inhibitory activity include penicillanic acid 1,1-dioxide (Barth, U.S. Pat. No. 4,234,579), various 6-beta-(hydroxymethyl)penicillanic 1,1-dioxides (Kellogg, U.S. Pat. No. 4,287,181), 6-alpha- and 6-beta-(benzylaminomethyl)penicillanic acid 1,1-dioxides (copending Barth, U.S. Ser. No. 388,323, filed June 14, 1982) and 6-alpha- and 6-beta-(aminomethyl)penicillanic acid 1,1-dioxides (copending Barth, U.S. Ser. No. 434,371, filed Oct. 21, 1982). Indeed, the compounds of the present invention find further utility as intermediates in an improved synthesis of said aminomethyl compounds of Barth.
The Grignard reagents derived from 6-alpha-bromopenicillanate 1,1-dioxide esters which are employed in the present invention are one of the objects of concurrently filed U.S. application, Ser. No. 501,476 for "Process for 6-(Aminomethyl)penicillanic Acid 1,1-Dioxide and Derivatives Thereof," by, now U.S. Pat. No. 4,502,990.